This project describes studies to examine the impact of HIV-1 sequence variation, cytokine and chemokine signaling, and cellular phenotype on the interaction of ATP/CREB and Sp factors with the LTR and the roles of these interaction during HIV-1 infection of defined CNS target cells. The preliminary studies show that the LTR sequence between the LEF-1 and NF-6B sites contains a binding site for members of the ATF/CREB transcription factor family. Using LTRs with mutant ATF/CREB sites, the preliminary studies show that changes in the ability of this site to bind cellular factors are reflected in changes in LTR activity in a cell type dependent manner which differs in cells of lymphocyte, monocyte, and astrocyte origin. The studies also suggest that members of the Sp transcription factor family may play a role in regulating HIV-1 gene expression in cells of the monocyte lineage. The specific aims are: 1) to define the functional role of ATF-CREB and Sp transcription factors in HIV LTR activation in transient expression assays in HIV-susceptible CNS target cells; 2) to define the functional role of ATF/CREB and Sp transcription factors in virus infection studies utilizing recombinant HIV infectious molecular clones in susceptible CNS target cells; 3) to define molecular mechanisms involved in ATF-CREB modulation of LEF-1 and NF-6B-mediated HIV-1 LTR activation as they relate to cell type specific gene expression and modulating viral load in the brain; 4) to define molecular mechanisms involved in Sp1/Sp3 LTR modulation as they relate to viral gene expression in cells of the monocyte/macrophage lineage, (including brain microglial cells) at different stages of cellular activation or differentiation.